16-methylene pregnene derivatives



United States Patent 16-METHYLENE PREGNENE DERIVATIVES Eugene J'. Agnello and Gerald D. Laubach, Jackson Heights, N. Y., assignors to Chas. Pfizer & 00., inc, Brooklyn, N.-Y., a corporation of Delaware No Drawing. Application June 9, 1958 Serial No. 740,598

7 Claims. (Cl. 167-65) (IIH2OR (3:0 7 l----H Y CH2 CH3 O: J

wherein X is. selected from the group consisting of hydrogen, halogen atoms, that is, fluorine, chlorine, bromine and iodine atoms and methoxy and ethoxy groups, Y is selected from the group consisting of keto and ,8- hydroxyl and R is selected from the group consisting of hydrogen and acyl hydrocarbon groups; an acyl hydrocarbon group being derived from mono and dicarboxylic acids containing up to twenty carbon atoms and alkali and alkaline earthmetal salts of these compounds when the. acyl group is derived from a dicarboxylic acid. The A A and A -derivatives of these compounds are also included within the purview of this invention.

A suitable starting compound for the preparation of the valuable therapeutic agents-of this-invention is represented by the formula H O. -O 0 (3011 ice prepared. The outline indicates the use of ethylene glycol for the formation of the diketals- It is apparent that other 1,2- and 1-,3-glycols such as 1,2-dihydroxy propane or 1,3-dihydroxy propane can also be employed.

imo o'oom omoo ooH, o=o o=o I- --OH |---OH no --o o'oona 00coH= omsozoi Y lHOBr 3550000113 rth-000011. o=o o=0 on l-- on --OOCCH H0 1 KOAc V k O O OCH;

1) Hydrolysis l OHaOH CH O'H 3) Reacetylate omoooon't onion" C Ketal C-Ketal L 0 L-- -0H T000011, Ton

'2)" Reaeetylatlon 3) KO A C l Quinone (Emoticon, omoooona C==O C=O 011 |---.0H no on, CH2

0X03 0 7 Pyridine O- Tlie usual methyl groups at the 18- and 19-positions are indicated by vertical lines for the sakeof simplicity.

In the first step of the synthesis of the valuable therapeutic agents of this invention, the'.16 ,21-diacetate prepared in accordance with, Allens procedure is dehydrated with methane sulfonyl chloride in pyridine according to known procedures illustrated in the appended examples to prepare a A -compound.'

The 9,8,11p-oxide is next prepared bytreating the A -compound first with N-bromoacetamide and perchloric acid in peroxide free dioxane. The resulting bromohydrin is treated with an alkaline reagent such as potassium acetate to convert the bromohydrin to the oxide; This procedure is fully illustrated in the appended samples.

The 3,20bis-diketal is next prepared. For this preparation the preceding diacetate is first hydrolyzed, then converted to a diketal and then reacetylated. These reactions are well known in the art and illustrated in the appended examples. 7

Alkaline hydrolysis of the resulting diketals yields a 16,21-diol. This reaction is carried out using, for example, 2 molar portions of potassium carbonate in aqueous methanol solution.

The 16,21-diol is next selectively acetylated at the 21-position. Although other acetylating agents can be used, it is preferred to use an equivalent of acetic anhydride in pyridine because of the ready availability of these compounds and the high yields which can be obtained by their use. Selective acylation at the 2l-position is a well known and simple reaction which can be readily carried out without concurrent acylation of the other hydroxyl groups in the molecule.

Conversion of the l6a-ol-2l-acetate to a 16-keto compound is readily accomplished with standard and well known oxidizing agents. It is preferred to use the chromic acid-pyridine complex since the reaction can be readily accomplished in high yields with minimum decomposition of starting material.

The 16-keto compound is nextreacted with the Wittig reagent, that is, triphenylphosphine-methylene. The reaction is well known. Its application to steroids is illustrated by Sondheimer and Mechoulam in the Journal of the American Chemical Society, ,vol. 79, page 5029. The application to the preparation of the valuable compounds of this invention is fully illustrated in the appended examples.

The 3,20-diketo-2'l-acetate of the compound previously prepared is then prepared by simultaneous hydrolysis of the ketal and acetate together with formation of a P 9,11-bromohydrin. This latter compound is converted to a 9,1l-oxide and reacetylated in accordance with standard procedures.

A double bond at the 6(7)-position is introduced by treatment of the above compound with a quinone having an oxidation-reduction potential less than 0.5 at a temperature between 70 C. and 190 C. in an inert organic solvent having a boiling point of at least about 70 C. Suitable solvents include mononuclear aromatic hydrocarbons, mononuclear halogenated aromatic hydrocarbons, oxygenated polar alicyclic organic solvents and oxygenated polar aliphatic organic solvents. Typical solvents include tertiary vbutanol, n-amyl alcohol, hexanol, isoamyl alcohol, heptanol, 3-cyclohexanol, orthdichloro benzene, xylene, tertiary amyl alcohol, secondary amyl alcohol, benzene, toluene, acetic acid, propionic acid, butyric acid, butyl acetate, amyl acetate, hexyl acetate, butyl propionate, propyl propionate, and amyl propionate. The application of this reaction to the preparation of M -androstadiene 9-halo compounds is illustrated in U. S. Patent No. 2,836,607, issued July 27, 1958. Its application to the preparation of the specific compounds of this invention is illustrated in the examples.

A double bond is introduced at the l(2)-position ot the preceding compound by contacting it with selenium dioxide in an inert organic solvent at an elevated temperature. Solvents which are useful for this reaction include, for example, tertiary butanol, tertiary pentanol, benzene, ethylene glycol diethers such as dibutyl Cellosolve, dipropyl ether, ethylene glycol and various other glycol ethers, phenetole, xylene, dioxane and naphthalene. Preferred conditions include the addition of a lower aliphatic acid particularly acetic acid to a tertbutanol mixture. In carrying out the reaction, it is generally preferred to utilize temperatures of from about C. to about 200 C. for from about 1 hour to about hours. Generally several molecular proportions of selenium dioxide are added during the reaction period. The application of this reaction is fully illustrated in copending patent application Serial No. 672,550, filed August 18,1957. Its application to the specific compounds of this invention is fully illustrated in the appended examples.

In the next step of the synthesisof the compounds of this invention, the 913,115-oxide ring is opened with a suitable reagent to produce a 9or-hal0 or a 9u-alkoxy, that is, methoxy or ethoxy compound having an hydroxyl group at'the ll-position. I These reactions are fully described by Fried et al. in the Journal of the Ameri can Chemical Society, vol. 79, page 1130. The application to the specific compounds of this invention are fully illustrated in the appended examples. The compounds prepared by these reactions are therapeutically active. 7

If desired, the llfi-hydroxyl group can be oxidized to an ll-keto group and compounds having this modification at the ll-position are also included within the purview of the invention. This oxidation can be carried out by any of a number of Well known procedures including oxidationwith chromium trioxide, sodium dichromate, N-bromoacetamide, and aluminum isopropoxide or aluminum tert-butoxide in the presence of a hydrogen acceptor such as acetone or cyclohexanone in an inert organic solvent such as benzene, toluene or xylene. It is preferred, however, to utilize the chromic acid-pyridine complex as the oxidizing agent since, as indicated above in connection with the oxidation of'the lfiu-hydroxyl group, the yields obtained are excellent.

It will be noted that the procedures described above produce compounds with either'a halogen or an alkoxy group at the 90t-POSltiOH. For the preparation of the compounds of this invention in which there is a hydrogen at the 9-position, a 9a-bromo compound prepared as described above is used. The bromine is removed using zinc and acetic acid by reactions well known in the art.

5 The procedure illustrated in he appended examples; T ynt e is, l s rated. abov n ut n d. pre ious Pr u d N -enmpo n s- Other compounds of the invention, that is, the A*-, the A and the A -compounds can be prepared by obvious modifications of this basic synthesis. Thus, to prepare a vn -compound, the 9fi,1 1-oxide ring is opened with the appropriate reagent Without resort to dehydrogenation with a quinone and selenium dioxide. For the preparation of the N -compound, the A -compound is treated with selenium dioxide only and for the preparation of the A -compound, only a quinone is used.

As will be recognized by those skilled in the art, there are modifications of this basic procedure which can be applied without essentially departing from the scope of the invention, for example, in the preparation of the A -compound selenium dioxide can be used before the application of the quinone reaction. As stated above, other dihydroxy compounds can be used to prepare the diketals. Esters other than acetates can be employed and alkaline hydrolysis reagents other than potassium carbonate are useful.

Although many of the reactions described above are applicable to compounds in which the 2l-position carries a free hydroxyl group, for optimum results it is best that the hydroxyl group be acylated with an acyl hydrocarbon group containing up to twenty carbon atoms. The term acyl hydrocarbon includes acyl hydrocarbon groups containing only carbon, hydrogen and oxygen derived from monocarboxylic or dicarboxylic acids. In the event that the acyl hydrocarbon group chosen is one derived from a dicarboxylic acid, it is often advantageous to treat the isolated therapeutically active compounds with abase derived from an alkali metal or alkaline earth metal to prepare a metal salt. These bases include, for example, sodium, potassium, barium and calcium hydroxide as Well as the corresponding carbonates and bicarbonates. Products so prepared are especially useful be cause of their increased solubility in water.

Since the 2l-position hydroxyl group is the only primary alcohol group present in any of the molecules whether starting material, intermediate or product, it may be readily esterified by standard methods. Although Fisher esterification and transesterification procedures may be employed, in general, it is preferred to form the esters by treatment with an acylating agent such as an acyl halide or anhydride in the presence of a tertiary base such as pyridine or dimethylaniline. Free alcohols are prepared from the corresponding esters by gentle hydrolysis, for example, by treatment with dilute potassium carbonate in aqueous methanol.

The biologically active compounds of this invention may be administered alone or in combination with acceptable pharmaceutical carriers, the choice of Which is determined by the preferred route of administration, the solubility of the compound and standard pharmaceutical practice. In general, the dosage of these compounds is of approximately the same order of magnitude as the dosage of hydrocortisone, and these compounds are useful to treat the types of pathological conditions often'treated with hydrocortisone. Because of their great adrenocortical activity it is sometimes possible to use dosages of these compounds which are lower than those of hydrocortisone.

For oraladministration the compounds may be administered in the form of tablets containing excipients such as starch or milk sugar. Aqueous suspensions andelixirs which may be sweetened or flavored may also be used. To apply thesetherapeutic agents topically, they may be prepared in the form of ointments and'salves in suitable bases especially non-aqueous petrolatum type bases. For intra-articular injection aqueous suspensions may be employed. In this case various suspending and wettlng agents may be added to the compositions to obtain a suspensionnot tending to settle. out easily or to pack *6 down in the bottle in which it is stored. Intramuscular and subcutaneous. dosage forms, may also be prepared by standard pharmaceutical practice.

The following examples are given solely for the purpose of illustration are not to be construed as limitations of this invention, many apparent variations of which are possible without departing from the spirit or scope thereof.

EXAMPLE I A -pregnadiene]6a,1 7a,21-tri0l-3,20-di0ne 16,21-diacetate A solution containing five g. of n -pregnenel1B,16a,l7u,21-tetrol-3,20-dione 16,2l-diacetate in 25 ml. of pyridine and 30 ml. of dimethylformamide is prepared. The solution is placed in a 3-necked flask to which is affixed a sealed stirrer, a dropping funnel and a condenser. The condenser and dropping funnel are protected with drying tubes. The mixture is cooled to -20 C. and a solution containing 4.6 ml. of methane sulfonyl chloride in five ml. of pyridine is added dropwise over a period of one hour with continued stirring. At the end of the hour, stirring is stopped, the reaction mixture allowed to come to room temperature and left standing for ten hours. At the end of this period, the solution is added dropwise to 750 ml. of ice cold water with stirring. The desired product precipitates and is recovered by filtration. It is dried and recrystallized from ethyl acetate.

EXAMPLE II 9u-br0m0-A -pregnene-1 1 13,,16oc,1,7oc,21 -tetr0l-3,20-dio.r1e 16,21-diacetate To a suspension of 500 mg. of the product prepared in the previous example in 25 ml. of pure peroxide free dioxane and .4 ml. of 0.46 N perchloric acid there is added in the dark at room temperature with stirring over a one hour period 114 mg. of solid N-bromoacetamide. At the end of 25' minutes, all ofthe starting material dissolves and 2.5 ml. of sodium sulfite solution is added with stirring. A few grams of ice in 20 ml. of chloroform is added and the layers separated. The organic layer is washed twice With water while maintaining the temperature at about 20" C. by the occasional addition of ice. The organic solution is concentrated in vacuo and acetone is added. The mixture is maintained at a temperature of about 5 C. until crystals form and the desired product is recovered by filtration.

EXAMPLE III Asolution ofj2.3- g. of the compound prepared in the previous example in ml. of dioxane is added to a solution of 15.8 g. of anhydrous potassium acetate in ml. of absolute alcohol at a temperature just below'the reflux temperature of thealcohol solution. The mixture is brought to reflux within 3 minutes and the reaction is After allowed to proceed for a total of 40'minutes. cooling in an ice bath, 400 ml. of ice water, is added with stirring andthe desired product-precipitates. Successive crops of the desired product may be. obtained by concentrating the mother liquor.

EXAMPLE IV 9,8,1 1B-oxido-M-pregnene-I6a,] 7a,21-triol-.i-,20-,di0ne 3,20-11 iethylene ketal 16,21-diacetate I 9,8,1 1fl-oxido-M-pregnene-I6a,] 7oz,21-tri0l-3,20-di0ne 3,20-dielhylene ketal The 16o:,21-acetate prepared as described in the previous example is hydrolyzed to the corresponding die] by the addition of 2 molar portions of potassium carbonate in a 10% aqueous methanol solution of the diester. Themixture is allowed to stand at room temperature for 1 hour and then poured into ice water to precipitate the desired diol.

EXAMPLE v1 93,1 1 fi-oxido-A pregnene-l 6 a,] 711,21 -tri0l-3,20-dione 3,2 O-diethylene ketal 21 -acetate A solution containing 1 g. of the 16,2l-diol prepared as described in the previous example in 25 ml. of pyridine containing a molar equivalent of acetic anhydride is allowed to stand at room temperature for 8 hours. The desired Zl-acetate is isolated in the conventional manner.

EXAMPLE VII 95,1 1;8-oxid0-A -pregnene-17u,21-diol-3,1 6 ,ZO-trione 3,2 O-diethylene ketal 21 -acetate To ml. of pyridine maintained at about 5 C. there is added 0.15 g. of chromic anhydride and the mixture allowed to warm spontaneously to room temperature. To this solution there is added 2 g. of the product prepared as described in the previous example in ml. of pyridine and the mixture permitted to stand at about C. for 24 hours. The solution is extracted with ether, the ether layer separated, washed twice with 5% aqueous hydrochloric acid at 10 C. and then with water. The organic layer is dried over anhydrous sodium sulfate, filtered and the desired product obtained by evaporation in vacuo.

EXAMPLE VIII 95,11,B-oxido-I6-methylene-A -pregnene-1 70521-11101- 3,20-di0r ze 3,20-diethylene keial 21-acetate A l N ethereal solution of butyl lithium (9 ml.) is added to a suspension of 3.6 g. of methyltriphenylphosphonium bromide (prepared from methyl bromide andtriphenylphosphine using the procedure described by Wittig in Ben, 87,1318 (1954), in 50 cc. of ether with swirling under nitrogen. The mixture is shaken in a nitrogen atmosphere for 2 hours and 0.5 equivalent of the product prepared in the previous example dissolved in 75 cc. of other is added. The mixture is shaken for 5 hours and left stand- EXAMPLE IX 95,1lfl-oxido-l6-methylene-M-prgnened70:,21-di0lv 3,20-di0ne 21 acetate A mixture of 1 g. of the compound prepared in the previous example together with 20 ml. of 46% aqueous hydrobromic acid and an equal volume of chloroform Cir is stirred vigorously at room temperature for 16 hours. The organic layer is separated, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. This product is reacetylated using the procedure described in Example VI and the residue is taken up in 40 ml. of dioxane and converted to the oxide using the procedure illustrated in Example III with appropriate quantities of reagents.

EXAMPLE X 9 3,] 1 fl-oxido-I 6-methylene-A -pregnadiene-1 7 a,21 dial-3,20-di0ne 21 -acetare A mixture containing 1.3 g. of the product prepared in the previous example and 3.0 g. of chloranil in 30 ml. tert-butanol is refluxed in a nitrogen atmosphere for 18 hours. The reaction mixture is then diluted with 250 ml. of chloroform. The solvent solution is washed with several small portions of 5% sodium hydroxide solution and then with water. It is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to leave the desired product as a residue.

EXAMPLE XI 913,1 1 fl-oxido-I 6-methylene-A -pregnatriene-I 7oc,21 dial-3,20-dione 21 -acetate A mixture of 0.8 g. of the product prepared in the previous example, 0.8 g. of selenium dioxide (freshly sublimed) and 10 ml. of t-butyl alcohol is heated in a nitrogen atmosphere for ten and one-half hours at 175 C. The solution is filtered and the desired product precipitated by the addition of water. It is isolated by filtration.

EXAMPLE )GI 9a-broma-1 6-methylene-A -pregnatrien e-] 1 18,1 7m,21- trial-3,20-a'i0ne ZI-acetate To a solution of 250 mg. of the product prepared in the previous example in 5 ml. of glacial acetic acid and 5 ml. of carbon tetrachloride, there is added 0.4 ml. of 32% hydrobromic acid in acetic acid. After 10 minutes at room temperature 100 ml. of chloroform is added and the solution washed twice with equal volumes of water. The organic layer is dried over anhydrous sodium sulfate, filtered and the desired product isolated by evaporating at reduced pressure.

EXAMPLE XIII 9u-ch loro-l 6-methylene-A -pregnatriene-l 1 19,1 7a,21- trial-3,20-di0ne 21 -acelate A solution of 4 g. of the compound prepared in Example XI in 40ml. of redistilled chloroform is prepared and 3.5 ml. of 0.45 N hydrogen chloride in chloroform solution is added over a 20 minute period. The reaction mixture is maintained at 0 C. for an additional hour. The chloroform solution is washed with water, separated, dried over anhydrous sodium sulfate, filtered and the desired product isolated by evaporation of the solvent in vacuo.

EXAMPLE XIV 9u-i0d0-16-methyZene-A -pregnatriene-1 1 6,1 711,21-

trial-3,20-di0ne 21 acetate A solution of 204 mg. of the compound prepared in Example XI in 20 ml. of chloroform is cooled to 20 C. and 0.4 ml. of aqueous hydriodic acid is added. The mixture is agitated for 20 minutes. Water is added, the organic layer separated and carefully evaporated in vacuo to leave a crystalline residue of the desired product which can be purified by recrystallization from ethyl acetate below 40 C.

EXAMPLE XV trial-3,20-di0ne 21-acetate Approximately 6 g; of anhydrous hydrogen fluoride is passed into a solution containing 51 g. of the compound prepared in accordance with the procedure of Example XlfirilOO ml. of redistilled chloroform at C, with constant stirring. The reaction mixture is maintained at this temperature for 2 hours and then made alkaline by the careful addition of aqueous sodium bicarbonate solution. The reaction mixture is extracted With chloroform, the organic layer dried over anhydrous sodium sulfate, filtered and the. filtrate, evaporated to leave the desired product as a residue.

EXAMPLE XVI 9o -methoxy-16-mezhylene-A -pregnatriene-I 1 5,1 7 (1,21 trial-3,20-di0ne 21 -ace tate A solution of the compound prepared as described in Example XI g.) in 250 ml. of methanol and 1.9 ml. of 72% perchloric acid is allowed to remain at room temperature for 4 hours. The solution is neutralized with aqueous sodium bicarbonate and the methanol removed in vacuo. The mixture is extracted with chloroform and the chloroform evaporated under reduced pressure to provide the desired compound as the free alcohol which is converted to the corresponding acetate by acetylation with 5 ml. of acetic anhydride in an equal volume of pyridine for 15 hours. The crystalline product is obtained byevaporation of the solvent in vacuo.

EXAMPLE XVII 9a-erh0xy-16-methylene-A -pregnatriene-l1,8,1 7a,21 tri0l-3,20-di0ne 21 -acetate A solution of the compound prepared using the procedure described in Example XI (5 g.) in 250 ml. of ethanol and 1.9 ml. of 72% perchloric acid is allowed to remain at room temperature for 4 hours. The solution is neutralized with aqueous sodium bicarbonate and the methanol removed in vacuo. The mixture is extracted with chloroform and the chloroform evaporated under reduced pressure to provide the desired compound as the free alcohol which is converted to the corresponding acetate by acetylation with 5 ml. of acetic anhydride in an equal volume of pyridine for 15 hours. The crystalline product is obtained by evaporation of the solvent in vacuo.

The procedure of Example XI is applied identically to the product of Example IX to prepare 95,11,8-oxid0-16- methylene-d -pregnadiene-17ot,21-diol-3,2O dione 21- acetate and this product is treated in accordance with the procedures set forth in Examples XII through XVII to prepare:

9OC-bI'OmO 16 methylene-A -pregnadiene 11f3,17a,21-

triol-3,20-dione 21-acetate 9 z-chloro 16 methylene-A -pregnadiene 1118,17 0t,21-

triol-3,20-dione 21-acetate 90c iodo 16 methylene A -pregnadiene 1lfi,l7a,21-

triol-3,20-dione 2l-acetate 9a-fil1010 16 methylene-A -pregnadiene 11 3,17a,2l-

triol-3,20-dione ZI-acetate 9a-methoxy 16 methylene-A -pregnadiene-l 15,17ot,21-

triol-3,20-dione 21-acetate 9u-ethoxy 16 methylene-A -pregnadiene 11B,17ot,21-

triol-3,2()-dione 21-acetate The procedures of Examples XII through XVII Were applied to the product of Example IX to prepare the following compounds.

9tx-bromo 16 methyIene-A pregnene 11,8,17a,21-triol- 3,20-dione 21-acetate 9a-chloro 16 methylene-M-pregnene 1lfi,17a,2l-triol- 3,20-dione 21-acetate 90a iodo 16 methylene-M-pregnene 11B,17a,21-triol- 3,20-dione 21-acetate 9a-fluoro 16 methylene-A -pregnene 11/8,17a,21-triol- 3,20-dione ZI-acetate 10 9u.-methoxy 16,- methylene-A -pregnene-lle,17a,21-triol 3,20-dione 21-acetate 9u-ethoxy 16 -rmethylene-A -pregnene.-.11p,17u,21-triol 3,20-dione 21-acetate The procedures of Examples XII through XVII were applied to the product of Example X to prepare the following compounds.

9a-bromo 16 methylene-A -pregnadiene- 11,8,17a,21-

triol-3,20-dione 21-acetate c chloro 16 methylene-A -pregnadiene 11/8,17u,21-

triol-3,20-dione 21-acetate 9a iodo 16 methylene A' -pregnadiene 1lfi,17a,21-

triol-3,20-dione 21-acetate 9u-fluoro 16 methylene A -pregnadicne 11B,17u,21-

triol-3,20-dione 21-acetate 9a-methoxy 16 methylene-A -pregnadiene-11,8,17u,21-

triol-3,20 -dione 21-acetate 9a-ethoxy 16 methylene-A -pregnadiene 11,8,17a,21

triol-3,20-dione 21-acetate EXAMPLE XVIII 9wbr0m0-16-methylens-A -pregnatriene-:,21-di0l- 3,11,20-trione 21 -acetate Chromic anhydride (0.125 g.) is added to 15 ml. of pyridine at about 5 C. and the mixture allowed to warm spontaneously to room temperature. To this solution is added 25 g. of 9a-bromo-16-methyleneA -pregnatriene-l1p,17a,21-triol-3,20-dione 21 acetate in 20 ml. of chloroform and the mixture allowed to stand at room temperature for 24 hours. The solution is extracted with ether and the organic layer washed twice with cold 5% aqueous hydrochloric acid and then with water. It is dried over anhydrous sodium sulfate, filtered and the desired product obtained by removal of the ether in vacuo.

The following compounds were prepared using the procedure of the above example. V

9a chloro 16 methylene-A -pregnatriene 1711,21-

diol-3,1 1,20-trione ZI-acetate 9a iodo 16 methylene A -pregnatriene 170:,21-

diol-3,11,20-trione ZI-acetate 90c fluoro 16 methylene A1145 pregnatriene-17a,2l-

diol-3,11,20-trione ZI-acetate 9ot-methoxy 16 methylene A pregnatriene-17a,21-

diol-3,11,20-trione 2l-acetate 9a ethoxy 16 methylene A1616 pregnatriene-17ot,21-

diol-3,l1,20-trione ZI-acetate 9a-bromo l6 methylene-A -pregnadiene 17oc,21-Cli0l 3,11,20-trione 21-acetate 90c-ChlOI'O 16 methylene-A -pregnadiene 17a,2l-diol- 3,11,20-trione 21-acetate 90c iodo 16 methylene-A -pregnadiene 170t,21 diol- 3,11,20-trione 21-acetate 9a-fluoro 16 methylene-A -pregnadiene 17a,21-diOl 3,11,20-trione ZI-acetate 9a-methoxy 16 methylene-A -pregnadiene-17a,21-diol- 3,1 1,20-trione 21-acetate 9a ethoxy 16 methylene-A -pregnadiene-l7ot,2l-diol- 3,11,20-trione Zl-acetate 9a-bromo 16 methylene-M-pregnene-170:,21-diol-3,11,

ZO-trione 21-acetate 9m chloro 16 methylene-M-pregnene-17ot,2l-diol-3,11,

20-trione 21-acetate 9a iodo 16 methylene-A' -pregnene-17a,21 diol-3,11,

ZO-trione 2l-acetate 90c fluoro 16 methylene-Abpregnene-17a,21-diol-3,11,

20-trione 21-acetate 9ot-rnethoxy 16-methylene-A -pregnene-17a,2l-diol-3,1l,

ZO-trione 2l-acetate 9ot-ethoxy 16 methylene-d -pregnene-17oz,21-diol-3,11,

20-trione 21-acetate 9abromo- 16- methylene- A pregnadiene- 17a,21 diol- 3,11,20-dione 21-acetate ice water to precipitate the free alcohols.

9m-Chl010- 16- methylene- A pregnadiene- 1741,21 diol- 3,11 .0- dione Zl-acetate 9u-l0d0- 16-- methylene 1A4,6 pregnadiene 17 ot,2l diol- 3,11,20-dione 21-acetate 9oc-flt10l'0- 16- methylene- A pregnadiene 170:,21 diol- 3,11,20-dione ZI-acetate 9amcthoxy-l6- methylene-A pregnadiene-17a,21- diol- 3,11,20-dione 21-acetate 91xethoxy-16- methylene- A pregnadiene- 17,21- diol- 3,11,20-dione ZI-acetate EXAMPLE XIX J 6 methylene A pregnatriene 1711,21 dial 3,11, 20-!rione 21 -acetate A solution containing 25 mg. of 9e-bromo-l6-methylone A pregnatriene 17a,2l diol 3,11,20 trionc ZI-acetate in 2 ml. of glacial acetic acid is treated portionwise with 48 mg. of zinc dust on the steam bath for a total of 15 minutes. The residual zinc was removed by configuration and the acetic acid solution evaporated to dryness in vacuo. The residue was recrystallized from acetone to yield the desired product in pure form.

This procedure was applied to other 9u-bromo compounds of this series to prepare corresponding A A and A compounds.

EXAMPLE XX 16 methylene A pregnatriene 115,17u,21 trial- 3,20-dine21-acetate A solution of 9vt-bromo-16methylene-A -pregnatriene-llfi,17u,21-triol-3,20-dione ZI-acetate (100 mg.) in a solution containing 30 ml. of water and ml. of alcohol was shaken with 1 g. of zinc dust at room temperature for 19 hours. The zinc dust is removed by centrifugation and washed with alcohol. The alcohol solution is concentrated in vacuo and the aqueous suspension extracted With chloroform. The residue from the chloroform extract is dissolved in 1:4 chloroform and benzene and chromatographed with silical gel (Davison No. 923, 2 g.). Elution of the column with 1:1 chloroform and benzene provides the corresponding M -compound (identified by its infrared spectra). The fraction containing this compound is followed by further fractions which are isolated by evaporation of the solvent and recrystallized from acetone to prepare the desired product.

7 This procedure was applied to other 9a bro-mo compounds of this series to prepare corresponding A A and A compounds.

EXAMPLE XXI The free 2l-alcohols of the esters prepared as in the previous examples are each prepared by hydrolysis using an equivalent of potassium carbonate in aqueous methanol solution. The mixture is allowed to stand at room temperature for one hour and then poured into EXAMPLE XXII A variety of 21-esters of the compounds prepared in accordance with the procedure of Examples XII through XX are each prepared by treating each of he free alcohols of Example XXI with acylating agents byconventional methods. These include such compounds as the formate, the propionate, the isobutyrate, the hexanoate, the benzoate, the octanoate, the stearate, the eicosanoate, the hemisuccinate, the trimethyl acetate, the cyclohexylcarhonate, the cyclopentylpropionate, etc. The acid esters such as the hemisuccinate have the advantage that alkali metal and alkaline earth metal salts are prepared from them by treating with molar proportions of a base such as sodium bicarbonate, potassium bicarbonate or calcium carbonate. These salts, in addition to being biologically active are water soluble, an advantage not possessed by the steroid alcohols themselves or by ordinary ester thereof.

What is claimed is: I

1. A compound selected from the group consisting of CH2 om and the A A and A -derivatives thereof wherein X is selected from the group consisting of hydrogen, whalogen, a-methoxy and a-ethoxy; Y is selected from the group consisting of keto and fl-hydroxy; 2l-position esters and acid esters thereof derived from mono and dicarboxylic acids containing only carbon, hydrogen and oxygen up to a total of twenty carbon atoms and alkali and alkaline earth metal salts of said acid esters.

2. A pharmaceutical composition comprising a compound as claimed in claim 1 together with a pharmaceutically acceptable carrier.

3. 9a fluoro 16 methylene A pregnene 11B,17 x, 21-triol-3,20-dione ll-acetate.

4. 9a fluoro l6 methylene A pregnene 17m, 2l-diol-3,11,20-trione 2 1-acetate.

5. 9a fluoro 16 methylene 11/3,17u,2l-triol-3,20-dione ZI-acetate. v

6. 9a fluoro 16 methylene A pregnadienc- 17o,21-diol-3,11,20-trione ZI-acetate.

7. 9oz fluoro 16 methylene A -pregnatriene-I1,9, l7u,2l-triol-3,20-dione ZI-acetate.

A pregnadiene- No references cited.

Notice of Adverse Decisien in Interference In Interference No. 92,246 involving Patent N 0. 2,865,808, E. J. Agnello and G. D. Laubach, 16-Methylene pregnene derivatives, final judgment adverse to the patentees Was rendered Oct. 16, 1968, as to claims 3, 4, 5 and 6.

[Ofiieial Gazette February 4, 1964.] 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF
 2. A PHARMACEUTICAL COMPOSITION COMPRISING A COMPOUND AS CLAIMED IN CLAIM 1 TOGETHER WITH A PHARMACEUTICALLY ACCEPTABLE CARRIER. 